Linking human cerebral and ocular waste clearance: Insights from tear fluid and ultra-high field MRI

Impaired cerebral waste clearance (i.e., glymphatics) is evident in aging and neurodegenerative disorders, such as Alzheimer's disease, where an impaired waste clearance system could be related to the accumulation of pathological proteins (e.g., tau). One marker of impaired cerebral clearance is the abundance of enlarged perivascular spaces (PVS). Preclinical studies propose a similar clearance system in the eye, driven by intraocular pressure (IOP). This cross-sectional pilot study explores the link between ocular and cerebral waste clearance by examining the association between MRI-visible PVS, tear fluid total-tau, and IOP. Thirty cognitively healthy participants, all aged over 55 years, underwent 7 Tesla MRI, with PVS visually rated in the centrum semiovale (CSO) and basal ganglia. Tear fluid was collected using paper Schirmer's strips and analyzed for total-tau using enzyme-linked immunosorbent assay. IOP was measured using non-contact tonometry. Partial Spearman's correlation coefficients of eye and brain markers were calculated, adjusted for age, sex, tear fluid-wetting length, and hemispheric region of interest volume. Higher CSO PVS scores in the left and right hemisphere were associated with higher levels of tear fluid total-tau. Higher CSO PVS scores in both hemispheres were related to lower ipsilateral IOP. The exploratory results suggest that higher tear fluid total-tau and a reduced driving force of ocular waste clearance are connected to impaired cerebral waste clearance in cognitive healthy individuals. This study connects the potential ocular glymphatic system to the cerebral waste clearance system. Clarifying waste clearance biology and validating eye biomarkers for cerebral waste clearance could provide treatment targets and diagnostic opportunities for neurological diseases.